The immunosuppressant drug cyclosporine A (CsA) has emerged as an important new cause of secondary hypertension and our previous work implicated a major neurogenic component in the pathogenesis. Using genetic mouse models, we recently showed that CsA raises blood pressure by stimulating renal sensory nerve endings containing synapsins, a family of vesicle-associated phosphoproteins that constitute putative substrates for calcineurin. In double knock out mice lacking synapsins I and II, renal sensory endings were normally developed but they were unresponsive to CsA. We now want to explore the molecular mechanism by which synapsins mediate CsA-induced renal afferent activation, and determine if targeted interruption of this novel mechanism confers protection against not only acute more importantly chronic CsA-induced hypertension. Our major new hypothesis is that calcineurin inhibition increases synapsin phosphorylation in renal sensory nerve endings, thereby accelerating exocytotic release of neurotransmiuers that act in an autocrine fashion to augment renal afferent discharge. We further hypothesize that this augmented in vivo autonomic response and the resultant hypertension are causally linked to two functionally important sites on the synapsin molecule: (1) one or more specific phosphorylation sites that constitute calcineurin substrates; and (2) the ATP binding site that is common to both synapsins. Using radiotelemetry to measure central aortic pressure in conscious unrestrained mice, our specfic aims are to determine if: (1) immunosuppressive doses of CsA produce chronic synapsin-dependent hypertension; (2) synapsin I or synapsin II is the principal isoform mediating this hypertension; (3) calcineunn is colocalized with synapsin in rena' sensory nerve endings by confocal microscopy and specific synapsiN phosphorylatiori sites constitute in vivo CsA-sensitive substrates for calcineurin in vagal nodosal ganglion neurons, (4) mutation in specific synapsin phosphorylation sites confers resistance against CsA-induced hypertension, and (5) mutation in the ATP binding site also confers resistance against CsA-induced hypertension.The distinctive features of this research include: (1) extensive phenotyping of transgenic mice to unravel a novel neural mechanism of hypertension; (2) elucidating an important role for synapsin-coated microvesicles in peripheral chemosensory transduction: and (3) providing a new conceptual framework for novel antihypertensive drug discovery to combat CsA-induced hypertension and other forms of refractory hypertension in which there is an important sympathetic component.